Targeting PPARα: A novel mechanism for deoxynivalenol-induced hepatic lipid accumulation and its mitigation by nobiletin

Deoxynivalenol (DON), a prevalent mycotoxin, disrupts hepatic lipid metabolism, but the mechanisms and potential mitigations are unclear. This study investigated DON-induced hepatic lipid accumulation and nobiletin's protective role. In HepG2 cells, non-cytotoxic DON (1-2 μM) increased lipid droplets, triglycerides (TG), non-esterified fatty acids (NEFA), and reactive oxygen species (ROS), while suppressing fatty acid oxidation (FAO) and ATP production. Sub-lethal DON exposure (20 μg/mL) induced hepatic steatosis in zebrafish larvae, elevating TG, total cholesterol (TC), and NEFA. Transcriptomic analysis revealed dysregulated lipid metabolism pathways, particularly PPAR signaling. Molecular docking and competitive binding assays confirmed DON directly binds PPARα (Kd = 8.31 μM). Nobiletin effectively reduced this binding affinity (Kd = 521 μM). Furthermore, nobiletin co-treatment mitigated DON-induced lipid accumulation in HepG2 cells by restoring FAO activity and ATP levels, and by attenuating the reduction of PPARα downstream target genes. Collectively, DON disrupts lipid metabolism and induces hepatic steatosis, at least partially, by binding PPARα. Nobiletin alleviates these effects by competing for PPARα binding and restoring metabolic homeostasis, highlighting its therapeutic potential against DON-induced hepatotoxicity. These findings highlight nobiletin's therapeutic potential and underscore the environmental significance of using targeted nutritional interventions against ubiquitous agricultural contaminants.